ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.916A>G (p.Ile306Val) (rs62642934)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel, RCV000169485 SCV000852135 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate).
Counsyl RCV000169485 SCV000220937 likely pathogenic Phenylketonuria 2014-12-05 criteria provided, single submitter literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089157 SCV000119771 not provided not provided no assertion provided not provided
Fulgent Genetics,Fulgent Genetics RCV000169485 SCV000611226 likely pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169485 SCV000696473 pathogenic Phenylketonuria 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The PAH c.916A>G (p.Ile306Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant was reported in numerous individuals in the literature, mainly associated with mild-PKU or hyperphenylalaninemia. In addition, in vitro assays show the variant to result in reduced PAH activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169485 SCV000833414 pathogenic Phenylketonuria 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 306 of the PAH protein (p.Ile306Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs62642934, ExAC 0.002%). This variant has been observed in multiple individuals affected with PAH-related disease as homozygous or in combination with other PAH variants  (PMID: 1358789, 18299955, 23430547, 23764561). ClinVar contains an entry for this variant (Variation ID: 618). Experimental studies have shown that this missense change impairs PAH enzyme activity in vitro (PMID: 25596310, 17924342, 11161839). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000649 SCV000020799 pathogenic Hyperphenylalaninemia, non-pku 1992-09-01 no assertion criteria provided literature only

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